Structure-activity relationships of HIV-1 PR inhibitors containing AHPBA - II. Modification of pyrrolidine ring at P1' proline

Article abstract of DOI:10.1016/0968-0896(96)00130-7

Systematic replacement in the 3- or 4-position of the pyrrolidine ring at P1' proline was carried out. Compound 26, which has a Cl atom in the 4(S)-position was the most active among inhibitors substituted with other halogen atoms or other substituents. Furthermore, the replacement of the Z group in compound 26 with five- or six-membered fused aromatic heterocycle carbonyl groups produced more potent inhibitors. 7-Methoxybenzofuran-2-carbonyl derivative (44) was the best of these and showed K(i) = 4.5 nM against HIV PR and IC₉₀s 0.58 μM and 0.06 μM in chronic and acute infections, respectively. These results suggest that the combination of the 4(S)-Cl atom and fused bicyclic heterocycles may be effective in improving their cellular penetration.